Sports Medicine Feature

Exercise Pill Causes Mice to Run for Salk Scientists

Biloine W. Young • Fri, May 12th, 2017

Scientists at the Salk Institute gave sedentary mice a pill containing a chemical compound that mimics the beneficial effects of exercise.

To their amazement, the mice who took the pill ran on a treadmill for 270 minutes. That was 70% longer than did mice who had not been given the pill.

Ronald M. Evans, Ph.D., senior author of the mice study, said, “It would take a lot of diligent training, every single day, to get that benefit. And these mice are getting it just because we’re feeding them a drug that’s reprogramming their metabolic properties.”

The key appears to be a gene called PPAR Delta (PPARD). When the PPARD genes in the mice were turned on, the mice could run for long distances without becoming exhausted. They were also resistant to weight gain and were responsive to insulin. The researchers said that the mice who took the pill had the properties of people who are physically fit.

The Salk scientists first developed a compound that they called GW1516. It appeared to activate the PPARD gene, but it did not incentivize the mice to run on their own.

The animals still had to train to be able to run long distances.

So the scientists doubled the dose of GW1516 and gave it to the mice for 8 weeks instead of just 4.

That did it. The mice began to run.

To find out what was happening at a genetic level they looked at 975 genes that seemed to change in response to GW1516. They found that the genes that became active were the ones involved in burning fat, while the genes that were suppressed were instrumental in turning carbohydrates into energy. They concluded that “PPARD is suppressing sugar metabolism in muscle, so glucose can be redirected to the brain.”

The Salk studies are designed to deal with the management of obesity, diabetes and other metabolic disorders. As for the exercise-in-a-pill idea, Evans’ team envisions “a prescription drug to help people with obesity or type 2 diabetes burn fat, and to make it easier for patients to become fit before or after surgery.”

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Found! Hormone Restores Muscle Function

Elizabeth Hofheinz, M.P.H., M.Ed. • Tue, June 21st, 2016

Columbia University researchers have found that when we exercise, our bones produce a hormone called osteocalcin that increases muscle performance. The work was just published in Cell Metabolism.

"Our bones are making a hormone called osteocalcin that provides an explanation for why we can exercise, " said Gerard Karsenty, M.D., Ph.D., a geneticist at the Columbia University Medical Center and senior author on the study, in the June 14, 2016 news release.

"The hormone is powerful enough to reconstitute, in older animals, the muscle function of young animals. Muscles and bones are close to each other, but it had never been shown before that bone actually influences muscle in any way."

As indicated in the news release, “The researchers observed that in 3-month-old adult mice, osteocalcin levels spiked approximately four times the amount that the levels in 12-month-old mice did when the rodents ran for 40 minutes on a treadmill. The 3-month-old mice could run for about 1, 200 meters before becoming exhausted, while the 12-month-old mice could only run half of that distance.”

“To investigate whether osteocalcin levels were affecting exercise performance, Karsenty and his colleagues tested mice genetically engineered so the hormone couldn't signal properly in their muscles. Without osteocalcin muscle signaling, the mice ran 20%-30% less time and distance than their healthy counterparts before reaching exhaustion.”

"It was extremely surprising that a single injection of osteocalcin in a 12-month-old mouse could completely restore its muscle function to that of a 3-month-old mouse, " said Karsenty.

Asked how far away we are from using osteocalcin in humans, Dr. Karsenty told OTW, “We need to look at other species; it is difficult to define a time table.”

Study: New Approach to Developing Bone-Forming Cells

Elizabeth Hofheinz, M.P.H., M.Ed. • Fri, June 19th, 2015

A protein known as “PPARy” just may help develop new bone-forming cells in patients who are losing bone. Researchers from the Florida campus of The Scripps Research Institute (TSRI) have created a novel approach that focused on the protein’s impact on stem cells derived from bone marrow. This work has just been published in Nature Communications.

According to the June 12, 2015 news release, “The scientists knew that a partial loss of PPARy in a genetically modified mouse model led to increased bone formation. To see if they could mimic that effect using a drug candidate, the researchers combined a variety of structural biology approaches to rationally design a new compound that could repress the biological activity of PPARy. The results showed that when human mesenchymal stem cells were treated with the new compound, which they called SR2595 (SR=Scripps Research), there was a statistically significant increase in osteoblast formation, a cell type known to form bone.”

“These findings demonstrate for the first time a new therapeutic application for drugs targeting PPARy, which has been the focus of efforts to develop insulin sensitizers to treat type 2 diabetes, ” said Patrick Griffin, Ph.D., chair of the Department of Molecular Therapeutics and director of the Translational Research Institute at Scripps Florida. “We have already demonstrated SR2595 has suitable properties for testing in mice; the next step is to perform an in-depth analysis of the drug's efficacy in animal models of bone loss, aging, obesity and diabetes.”

Dr. Griffin told OTW, “We expected our compounds to be neutral on bone or perhaps slightly positive on bone, but the effects are much more pronounced. We see a clear impact on bone turnover and bone density.”

“We have a new manuscript under review at a high impact journal that shows the positive effects on bone in obese mice. Because it takes a long time from submission to acceptance the animal work has been completed already—and we are very excited indeed.”

Crippled Mice Walk in Swiss Lab Experiments

Biloine W. Young • Thu, February 5th, 2015

Two Swiss researchers at the Ecole Polytechnique Federale in Lausanne, Switzerland, had already earned the world’s plaudits when they created an implanted device that allowed paralyzed mice to move their legs. When Gregoire Courtine and Stéphanie Lacour later discovered that their ground-breaking new device eventually caused compression and tissue damage in their subjects because it was too stiff, they decided to invent a flexible implant.

According to Joseph Keenan, FierceMedical Devices, writing on a study from MIT Technology Review, they succeeded. To prevent the damage caused by the rigid implant they invented a flexible product they call an “e-dura” which has a property of human tissue called viscoelasticity. Made of soft silicone, gold wires and rubbery electrodes flecked with platinum, the device is both stretchable and flexible and can be wrapped around the spinal cords of mice. The device also contains a channel that allows the scientists to introduce drugs and medications to the injury site.

When the researchers sent electrical signals through the e-dura, which they had wrapped around the animal’s spinal cord, the mice’s hind legs moved. After a two month period, the mice showed little sign of any tissue damage—which had not been the case earlier when they had experimented with conventional electrodes.

Keenan quoted Lacour, who is an electrical engineer, as telling MIT, "If you want a therapy for patients, you want to ensure it can last in the body. If we can match the properties of the neural tissue we should have a better interface."

The aim of their research, of course, is to create an implant that could restore a paralyzed person’s ability to walk. That goal is probably a long way off but Lacour believes that, when it does come, it will involve soft electronics.

Discovered! Gene That Causes Rare Bone Disease

Elizabeth Hofheinz, M.P.H., M.Ed. • Thu, January 21st, 2016

Rare and painful, a little-known disease known as Hajdu-Cheney syndrome is garnering some attention. Along with colleagues, a researcher from the University of Connecticut (UConn) has discovered the gene that causes Hajdu-Cheney, an affliction that causes the softening—and fracture—of bones.

Using a mouse model, Ernesto Canalis, M.D. and colleagues targeted a gene known as NOTCH2. According to the January 14, 2016 news release, “…this gene has a specific mutation that appears in people with the syndrome.”

As stated in the news release, “His mice seem to provide the answers. They generate a larger pool of osteoclasts, cells that break down and resorb old bone. These cells also mature faster than they do in normal mice. So Hajdu-Cheney mice have far too much bone resorbed by their bodies, and new bone doesn't grow fast enough to replace it. This leads to mice with fragile bones, very similar to people with the disease.”

"Until now, nobody understood why people afflicted with the disease had osteoporosis and fractures, " said Dr. Canalis, a professor of orthopedic surgery at UConn Health.

As indicated in the news release, “Hajdu-Cheney is an incredibly rare disease, with fewer than 100 cases ever described. But there are good scientific reasons to study it. It can illuminate the workings of bone formation and destruction, and give insight into a gene important to both the skeleton and the immune system. It could also possibly tell us about Alagille syndrome, another, much more common genetic disease associated with NOTCH2.”

Dr. Canalis told OTW, “We were able to recreate the NOTCH2 mutation found in humans in mice. We were able to establish a mutant mouse colony and studied the skeleton of the mice. We learned that mice with a Hajdu-Cheney mutation exhibited selected aspects of the human disease and developed significant bone loss, at cortical and trabecular sites. We were surprised to learn that the phenotype was due to a higher number of bone resorbing cells that had a greater capacity to differentiate and resorb bone. The results provide a mechanism for the disease and may serve to suggest appropriate therapeutic interventions.”

New Growth Factor Reverses Osteoporosis in Mice

Elizabeth Hofheinz, M.P.H., M.Ed. • Tue, December 27th, 2016

Researchers from the Children's Medical Center Research Institute at The University of Texas Southwestern (CRI) have discovered a new bone-forming growth factor, Osteolectin (Clec11a), which reverses osteoporosis in mice.

As indicated in the December 13, 2016 news release, “Although Osteolectin is known to be made by certain bone marrow and bone cells, CRI researchers are the first to show Osteolectin promotes the formation of new bone from skeletal stem cells in the bone marrow. The study, published on December 13, 2016 in eLife, also found that deletion of Osteolectin in mice causes accelerated bone loss during adulthood and symptoms of osteoporosis, such as reduced bone strength and delayed fracture healing.”

"These results demonstrate the important role Osteolectin plays in new bone formation and maintaining adult bone mass. This study opens up the possibility of using this growth factor to treat diseases like osteoporosis, " said Sean Morrison, Ph.D., who led the team that made the discovery. Dr. Morrison, CRI Director, holds the Mary McDermott Cook Chair in Pediatric Genetics at UT Southwestern Medical Center, and the Kathryne and Gene Bishop Distinguished Chair in Pediatric Research at Children's Research Institute at UT Southwestern.

Dr. Morrison told OTW, “We have been characterizing the microenvironment in the bone marrow to better understand the mechanisms that regulate the function of blood-forming and bone-forming stem cells in adult bone marrow. We discovered that Osteolectin is produced by the same cells that secrete the factors that promote the maintenance of both kinds of stem cells. To test whether Ostelectin encodes an undiscovered growth factor activity we generated knockout mice. The mice were born in normal numbers, appeared to be developmentally normal, and had normal hematopoiesis but exhibited acclerated bone loss during aging—they developed early onset osteoporosis. This told us that Osteolectin is required for the maintenance of the adult skeleton. We went on to show that Osteolectin maintains the adult skeleton by promoting the differentiation of skeletal stem cells into mature osteoblasts.”

“Osteolectin is a new anabolic, bone-forming growth factor. Administration of Osteolectin to mice with osteoporosis systemically promotes for the formation of new bone.